Schreiber Stefan, Khaliq-Kareemi Mani, Lawrance Ian C, Thomsen Ole Østergaard, Hanauer Stephen B, McColm Juliet, Bloomfield Ralph, Sandborn William J
Hospital for General Internal Medicine, Christian Albrechts University, Kiel, Germany.
N Engl J Med. 2007 Jul 19;357(3):239-50. doi: 10.1056/NEJMoa062897.
Certolizumab pegol is a pegylated humanized Fab' fragment with a high binding affinity for tumor necrosis factor alpha that does not induce apoptosis of T cells or monocytes.
In our randomized, double-blind, placebo-controlled trial, we evaluated the efficacy of certolizumab pegol maintenance therapy in adults with moderate-to-severe Crohn's disease. As induction therapy, 400 mg of certolizumab pegol was administered subcutaneously at weeks 0, 2, and 4. Patients with a clinical response (defined as reduction of at least 100 from the baseline score on the Crohn's Disease Activity Index [CDAI]) at week 6 were stratified according to their baseline C-reactive protein level and were randomly assigned to receive 400 mg of certolizumab pegol or placebo every 4 weeks through week 24, with follow-up through week 26.
Among patients with a response to induction therapy at week 6 (428 of 668 [64%]), the response was maintained through week 26 in 62% of patients with a baseline C-reactive protein level of at least 10 mg per liter (the primary end point) who were receiving certolizumab pegol (vs. 34% of those receiving placebo, P<0.001) and in 63% of patients in the intention-to-treat population who were receiving certolizumab pegol (vs. 36% receiving placebo, P<0.001). Among patients with a response to induction therapy at week 6, remission (defined by a CDAI score of < or =150) at week 26 was achieved in 48% of patients in the certolizumab group and 29% of those in the placebo group (P<0.001). The efficacy of certolizumab pegol was also shown in patients taking and those not taking glucocorticoids or immunosuppressants and in patients who had and those who had not previously taken infliximab. Infectious serious adverse events (including one case of pulmonary tuberculosis) occurred in 3% of patients receiving certolizumab pegol and in less than 1% of patients receiving placebo. Antinuclear antibodies developed in 8% of the patients in the certolizumab group; antibodies against certolizumab pegol developed in 9% of all patients who entered the induction phase.
Patients with moderate-to-severe Crohn's disease who had a response to induction therapy with 400 mg of certolizumab pegol were more likely to have a maintained response and a remission at 26 weeks with continued certolizumab pegol treatment than with a switch to placebo. (ClinicalTrials.gov number, NCT00152425 [ClinicalTrials.gov].).
赛妥珠单抗聚乙二醇化修饰是人源化Fab'片段，对肿瘤坏死因子α具有高结合亲和力，不会诱导T细胞或单核细胞凋亡。
在我们的随机、双盲、安慰剂对照试验中，我们评估了赛妥珠单抗聚乙二醇化修饰维持治疗对中度至重度克罗恩病成人患者的疗效。作为诱导治疗，在第0、2和4周皮下注射400mg赛妥珠单抗聚乙二醇化修饰。在第6周有临床反应（定义为克罗恩病活动指数[CDAI]较基线评分至少降低100）的患者，根据其基线C反应蛋白水平进行分层，并随机分配接受每4周一次400mg赛妥珠单抗聚乙二醇化修饰或安慰剂，直至第24周，并随访至第26周。
在第6周对诱导治疗有反应的患者中（668例中的428例[64%]），对于基线C反应蛋白水平至少为每升10mg的患者（主要终点），62%接受赛妥珠单抗聚乙二醇化修饰的患者至第26周反应得以维持（接受安慰剂的患者为34%，P<0.001）；在意向性治疗人群中，63%接受赛妥珠单抗聚乙二醇化修饰的患者至第26周反应得以维持（接受安慰剂的患者为36%，P<0.001）。在第6周对诱导治疗有反应的患者中，赛妥珠单抗组48%的患者在第26周达到缓解（定义为CDAI评分≤150），安慰剂组为29%（P<0.001）。赛妥珠单抗聚乙二醇化修饰的疗效在服用和未服用糖皮质激素或免疫抑制剂的患者中以及在既往使用和未使用英夫利昔单抗的患者中均得到体现。接受赛妥珠单抗聚乙二醇化修饰的患者中有3%发生感染性严重不良事件（包括1例肺结核），接受安慰剂的患者中发生率不到1%。赛妥珠单抗组8%的患者出现抗核抗体；进入诱导期的所有患者中有9%产生了抗赛妥珠单抗聚乙二醇化修饰抗体。
与改用安慰剂相比，中度至重度克罗恩病患者在接受400mg赛妥珠单抗聚乙二醇化修饰诱导治疗有反应后，继续接受赛妥珠单抗聚乙二醇化修饰治疗在26周时更有可能维持反应并实现缓解。（临床试验注册号，NCT00152425 [ClinicalTrials.gov]。）
